17.9 : Senescência Celular Replicativa

Replicative cell senescence is a property of cells that allows them to divide a finite number of times throughout the organism's lifespan while preventing excessive proliferation. Replicative senescence is associated with the gradual loss of the telomere — short, repetitive DNA sequences found at the end of the chromosomes. Telomeres are bound by a group of proteins to form a protective cap on the ends of chromosomes. Embryonic stem cells express telomerase — an enzyme that adds the telomeric repeat sequence and enables repetitive cell division; however, in adults, telomerase is active only in the cells that need to divide regularly.

Because telomerase is inactive in most human somatic cells, the length of the telomere decreases with every cell division. After a critical length, telomere shortening leads to permanent cell cycle arrest. This mechanism is assumed to protect against cancer development by limiting the abnormal proliferation of tumors; however, a rare mutation can activate telomerase, which reconstructs the telomere region, allowing the cells to proliferate. Thus, telomerase is a perfect target for specific anticancer therapy, as most cancer cells express telomerase while normal cells do not.

The relation between telomere length and tumor formation has been experimentally verified using oncogenic mice. Oncogenic mice are mouse models that have cancer-causing genes. When such oncogenic mice are crossed with telomerase-deficient mice that lack telomerase activity, the resultant progeny mice express shorter telomeres than the oncogenic parent. These progeny mice, when interbred, generate successive generations that have progressively shorter telomeres. The frequency of tumor formation is studied by treating the progeny mice with carcinogens at every generation. As per the results, the late generation mice with shorter telomeres exhibit a reduced frequency of tumor formation compared to the early generation mice that maintain longer telomeres. This proves that limiting the replicative capacity of cells suppresses tumor formation.